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Using the body clock to make drugs more effective

Researchers created a database for the daily circadian rhythms of genetic activity. The findings may help physicians time the delivery of drugs in accordance with a person's body clock, boosting treatment for cardiovascular disease and other conditions.

More recently, scientists have found links between sleep-wake cycle disruptions and the onset of Alzheimer's disease.

Conversely, specialists use chronotherapy — or the process of progressively adjusting a person's bedtime and waking time — to time the delivery of drugs so that it falls in line with circadian changes.

In conditions such as cardiovascular disease or high blood pressure, for example, chronotherapy has proven useful because some cardiovascular diseases — such as heart attacks, angina, and stroke — have a higher incidence in the morning.

More recent research also suggests that our body clock — or the collection of proteins that interact within cells, regulating cellular activity and their corresponding genetic expressions — plays a key role in cancer, and that chronotherapy could boost the effectiveness of cancer treatment.

In this context, researchers led by John Hogenesch, Ph.D. — a circadian biologist in the Divisions of Human Genetics and Immunobiology at the Cincinnati Children's Hospital Medical Center in Ohio — set out to create a database of daily genetic rhythms.

Some of these genes can control the activity of drugs, which makes for an important contribution to the growing field of circadian medicine.

The researchers detail their efforts in the journal Science Translational Medicine, and Marc Ruben, Ph.D., is the first author of the paper.

Using cycling genes as drug targets

Hogenesch and team created a computer algorithm called cycling ordering by periodic structure to study how circadian rhythms control the changes in gene activity that occur throughout the day.

Specifically, the researchers used the algorithm to study the gene-to-tissue interactions of thousands of genes in the tissues of over 630 human participants.

Of all the genes studied, 917 expressed proteins that help metabolize and absorb drugs, or that are drug targets themselves.

"Overall this connects thousands of different drugs, both approved and experimental, to nearly 1,000 cycling genes [...] We found that genes that cycle in the human cardiovascular system are targeted by many of these drugs."

Marc Ruben, Ph.D.

According to the study authors, the genes for 136 drug targets were found to cycle rhythmically in at least one of the following four heart tissues: the atrial chamber, aorta, coronary artery, and the tibial artery.

"We identified rhythms in gene expression across the body in a large and diverse group of people," explains Hogenesch. "It doesn't matter if you're male, female, young, or old, or what your ethnicity is, your body's internal clock regulates half your genome."

"This includes drug-metabolizing enzymes, transporters, and targets," he says. "Now we are learning which drugs hit clock-regulated products and may benefit from optimizing administration time in people."

Hogenesch cautions that more research is required before the findings can be applied to clinical practice.

However, "As most of these drugs are safe and approved, this process should go much faster than traditional drug discovery, which can take a decade or more," he concludes.

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